The present invention relates to eyedrops for promoting lacrimal secretion or treating keratoconjunctival disorders containing a natriuretic peptide as an active ingredient.
A lacrimal fluid, which has a mechanism to retain wettability on living bodies, covers cornea and conjunctiva (keratoconjunctiva), retains wettability and prevents them from drying. The lacrimal fluid works as a lubricant protecting the keratoconjunctiva from stimulation by blinking and contributes to retaining smoothness of the corneal surface. The lacrimal fluid has bacteriostasis, prevents infection from bacteria, fungus, virus and the like, supplies oxygen and a variety of nutrition to the cornea and removes a carbon dioxide gas and metabolites. When the keratoconjunctiva is disordered, the lacrimal fluid plays a role to dilute and remove disordering stimuli, and works to carry liquid components such as epidermal growth factors participating in wound healing and hematocyte components such as fibronectin to disordered sites. That is, the lacrimal fluid participates in adjusting wound healing as well as retaining keratoconjunctival epithelial cells. Thus, it is known that the lacrimal fluid, though its amount is very small, adjusts a physiological condition of the keratoconjunctiva, and thereby maintaining transparency and homeostasis of the cornea (Journal of the Eye, 11, 1179-1185 (1994)).
Known methods of treating keratoconjunctival disorders such as dry eye (keratoconjunctivitis sicca and the like) are a method of supplying lacrimal fluid components with artificial tears, a method of retaining a lacrimal fluid remaining on the keratoconjunctiva surface with a viscoelastic substance to lead to treating the keratoconjunctiva and the like. Since the lacrimal fluid exhibits the above-mentioned effect of curing the keratoconjunctival disorders, it is expected that finding compounds acting on a lacrimal gland function directly and promoting lacrimal secretion is useful for curing corneal erosion, corneal ulcer and the like having keratoconjunctival epithelial disorders such as dry eye.
Peptides belonging to natriuretic peptides are widely distributed in mammal, birds, amphibians and fish and are classified into three groups, namely atrial natriuretic peptides (ANP), brain natriuretic peptides (BNP) and C-type natriuretic peptides (CNP), according to structure. Known atrial natriuretic peptides (ANP) are xcex1-ANP consisting of 28 amino acids, xcex1-ANP [4-28] consisting of 4th to 28th amino acids of xcex1-ANP, xcex1-ANP [5-28] consisting of 5th to 28th amino acids of xcex1-ANP, xcex2-ANP having an antiparallel dimer structure of xcex1-ANP, high-molecular type xcex3-ANP having molecular weight of 13,000 formed by cutting out a signal peptide from an ANP precursor and the like. Known brain natriuretic peptides (BNP) are BNP-26 consisting of 26 amino acids, BNP-32 consisting of 32 amino acids, BNP-45 consisting of 45 amino acids, high-molecular type xcex3-BNP having molecular weight of about 13,000 formed by cutting out a signal peptide from a BNP precursor and the like. Known C-type natriuretic peptides (CNP) are CNP-22 consisting of 22 amino acids, CNP-53 consisting of 53 amino acids extending to the N-terminal and the like. These natriuretic peptides act on kidneys, adrenalglands and vascular walls and play an important role in adjusting electrolytes in a general body fluid and blood pressure (xe2x80x9cPeptides Adjusting Circulation and Related Diseasesxe2x80x9d, p. 14-25, Youdosha, 1992).
xcex1-ANP has a vasodilatory action and a diuretic action and is used as a therapeutic agent for cardiovascular diseases such as heart failure (Jpn. Pharmacol. Ther., 23, 949-952 (1995)).
In an ophthalmological field, it was reported that xcex1-ANP exhibits an effect of lowering intraocular pressure (Curr. Eye Res., 6, 1189-1196 (1987)). However, other effects of xcex1-ANP have scarcely been studied, and there have been no literature which reports effects of the natriuretic peptides on lacrimal gland and the keratoconjunctival disorders by instillating them.
Few application studies of the natriuretic peptides to the ophthalmological field have been done except for the study on the effect of lowering intraocular pressure. It is a very interesting subject to study new effects of the natriuretic peptides in the ophthalmological field.
Studying precisely in order to find new effects of natriuretic peptides in an ophthalmological field, the present inventors found that the natriuretic peptides exhibit effects of promoting lacrimal secretion and are useful as therapeutic agents for keratoconjunctival disorders.
The present invention relates to eyedrops for promoting the lacrimal secretion and treating the keratoconjunctival disorders containing the natriuretic peptide as an active ingredient.
The natriuretic peptides are atrial natriuretic peptides (ANP), brain natriuretic peptides (BNP) and C-type natriuretic peptides (CNP) in the present invention. ANP, BNP and CNP having different structures are known, and the natriuretic peptides of the present invention include all of them.
The natriuretic peptides are useful drugs as therapeutic agents for cardiovascular diseases, but few effects have been reported other than their effects of lowering intraocular pressure in an ophthalmological field.
Studying application of the natriuretic peptides to the ophthalmological field, the present inventors found that when the natriuretic peptides are instilled into rabbits, the natriuretic peptides exhibit excellent effects of promoting the lacrimal secretion. Details will be described in the part of xe2x80x9cPharmacological Testxe2x80x9d. Since the lacrimal fluid exhibits the effect of curing the keratoconjunctival disorders as described in detail in the part of xe2x80x9cBackground Artxe2x80x9d, the present drugs are expected to be useful as the therapeutic agents for the keratoconjunctival disorders. Typical examples of the keratoconjunctival disorder are dry eye, corneal erosion and corneal ulcer.
The eyedrops of the present invention can be prepared by dissolving the natriuretic peptide in a general ophthalmic vehicle in using the eyedrops. The eyedrops can be formulated by adding optionally a suitable amount of an isotonic agent such as sodium chloride or concentrated glycerin, a buffer such as sodium phosphate or sodium acetate, a surfactant such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate or polyoxyethylene hydrogenated castor oil, a stabilizer such as sodium citrate or disodium edetate, a preservative such as benzalkonium chloride or paraben or the like. pH can be in the range acceptable to ophthalmic preparations and is preferably in the range of 4 to 8.
A concentration of the active ingredient in the eyedrops is 0.001 to 1% (W/V), preferably 0.005 to 0.5% (W/V), more preferably 0.05 to 0.5% (W/V). The eyedrops are administered by instilling one to several times per day.